Stephen J. Cleland

Risk of cardiovascular disease and total mortality in adults with type 1 diabetes: Scottish registry linkage study

Helen Colhoun and colleagues report findings from a Scottish registry linkage study regarding contemporary risks for cardiovascular events and all-cause mortality among individuals diagnosed with type 1 diabetes.

Insulin Action Is Associated With Endothelial Function in Hypertension and Type 2 Diabetes

A primary defect in the vascular action of insulin may be a key intermediate mechanism that links endothelial dysfunction with reduced insulin-mediated cellular glucose uptake in metabolic and cardiovascular disorders. The present study was designed to characterize more fully the relations between insulin action and endothelial function in male patients with essential hypertension (H, n=9) or type 2 diabetes (D, n=9) along with healthy control subjects (C) matched for age, body mass index, and lipid profile. They attended for measurement of whole-body insulin sensitivity (MCR) by the hyperinsulinemic clamp technique (day 1) and forearm vasoreactivity in response to intra-arterial infusions of insulin/glucose (day 2) and N(G)-monomethyl-L-arginine (L-NMMA) and norepinephrine (day 3) by bilateral venous-occlusion plethysmography. Results expressed as mean+/-SE MCR (mL/kg per minute) were 7.22+/-0. 99 (C), 6.32+/-0.78 (H), and 5.06+/-0.53 (D). Insulin/glucose-mediated vasodilation (IGMV) was 17.1+/-5.6% (C), 17. 2+/-5.5% (H), and 12.3+/-6.4% (D). L-NMMA vasoconstriction (LNV) was 37.9+/-5.1% (C), 37.5+/-2.3% (H), and 33.6+/-2.8% (D). There were no significant differences among groups for these parameters. Pooled correlation analyses revealed associations between MCR and IGMV (r=0. 46, P<0.05), MCR and LNV (r=0.44, P<0.05), and IGMV and LNV (r=0.52, P<0.01). This study supports functional coupling between insulin action (both metabolic and vascular) and basal endothelial nitric oxide production in humans.

Serial Metabolic Measurements and Conversion to Type 2 Diabetes in the West of Scotland Coronary Prevention Study Specific Elevations in Alanine Aminotransferase and Triglycerides Suggest Hepatic Fat Accumulation as a Potential Contributing Factor

To examine metabolic changes (lipids, liver enzymes, blood pressure, and weight) potentially associated with conversion to diabetes, we analyzed serial glucose and other metabolic measures obtained every 6 months within the West of Scotland Coronary Prevention Study trial. Changes in parameters for 86 men who converted to new-onset diabetes (“converters”: two consecutive glucose levels ≥7 mmol/l) were compared with 860 “nonconverters” matched for age and treatment allocation. Eighteen months before the diagnosis, converters to diabetes had elevated (P < 0.01) fasting glucose, weight, triglyceride, alanine aminotransferase (ALT), blood pressure, and white cell count and lower HDL cholesterol compared with nonconverters. The mean (SD) increase in fasting glucose over 18 months in converters was 1.80 (1.52) mmol/l, compared with 0.10 (0.57) in nonconverters. Of parameters measured, only ALT (P = 0.0005) and triglyceride (P = 0.030) increased significantly more over the 18 months in converters compared with nonconverters, but neither parameter increased significantly in nonconverters with high baseline glucose concentrations (>6.1 mmol/l). Finally, only sustained increases in ALT predicted a higher risk for diabetes. We conclude that a relatively rapid rise in fasting glucose levels is frequent in converters to diabetes and that associated increases over time in ALT and potentially triglyceride suggest hepatic fat accumulation as a contributing factor for conversion to diabetes in men at risk.

Insulin as a vascular hormone: Implications for the pathophysiology of cardiovascular disease

1. Metabolic disorders, such as obesity and non‐insulin‐dependent diabetes mellitus, and cardiovascular disorders, such as essential hypertension, congestive cardiac failure and atherosclerosis, have two features in common, namely relative resistance to insulin‐mediated glucose uptake and vascular endothelial dysfunction.

Rosiglitazone Stimulates Nitric Oxide Synthesis in Human Aortic Endothelial Cells via AMP-activated Protein Kinase

The thiazolidinedione anti-diabetic drugs increase activation of endothelial nitric-oxide (NO) synthase by phosphorylation at Ser-1177 and increase NO bioavailability, yet the molecular mechanisms that underlie this remain poorly characterized. Several protein kinases, including AMP-activated protein kinase, have been demonstrated to phosphorylate endothelial NO synthase at Ser-1177. In the current study we determined the role of AMP-activated protein kinase in rosiglitazone-stimulated NO synthesis. Stimulation of human aortic endothelial cells with rosiglitazone resulted in the time- and dose-dependent stimulation of AMP-activated protein kinase activity and NO production with concomitant phosphorylation of endothelial NO synthase at Ser-1177. Rosiglitazone stimulated an increase in the ADP/ATP ratio in endothelial cells, and LKB1 was essential for rosiglitazone-stimulated AMPK activity in HeLa cells. Infection of endothelial cells with a virus encoding a dominant negative AMP-activated protein kinase mutant abrogated rosiglitazone-stimulated Ser-1177 phosphorylation and NO production. Furthermore, the stimulation of AMP-activated protein kinase and NO synthesis by rosiglitazone was unaffected by the peroxisome proliferator-activated receptor-γ inhibitor GW9662. These studies demonstrate that rosiglitazone is able to acutely stimulate NO synthesis in cultured endothelial cells by an AMP-activated protein kinase-dependent mechanism, likely to be mediated by LKB1.

Insulin-Mediated Vasodilation and Glucose Uptake Are Functionally Linked in Humans

Intra-arterial infusion of insulin in physiological doses causes forearm vasodilation which is augmented by co-infusion of D-glucose, leading us to speculate that local insulin-mediated vasodilation may depend on insulin-mediated glucose uptake. We have examined the relationship between whole-body insulin sensitivity and forearm vasodilation in response to local infusion of insulin/glucose, thus avoiding any confounding effects of sympathetic stimulation on peripheral blood flow. Eighteen healthy, normotensive male volunteers (age, 26+/-5.4 years) attended on two separate occasions for measurement of: (1) whole-body insulin sensitivity with use of the hyperinsulinemic euglycemic clamp; (2) forearm vasodilation in response to an intra-arterial infusion of insulin/glucose with use of bilateral venous occlusion plethysmography. Insulin-mediated glucose uptake (M) for the group (mean+/-SD) was 10.0+/-2.2 mg. kg-1. min-1, and the percentage change in forearm blood flow ratio (%FBFR) for the group (median, interquartile range) was 28.2% (13.6, 48.6). In univariate analysis, M was significantly correlated with %FBFR (rs=0.60, P<0.05), but not with body mass index (BMI) (rs=-0. 42), age (r=-0.39) or mean arterial pressure (r=0.13). In multiple regression analysis, %FBFR remained a significant independent predictor of M (R2 (adj)=0.48, t=3.23, P<0.01) in a model involving BMI, age, and blood pressure. These data support the concept of a significant functional relationship between insulins metabolic and vascular actions, possibly at an endothelial level.

Effects of Diabetes Family History and Exercise Training on the expression of Adiponectin and Leptin and their Receptors

Daughters of diabetes patients have lower insulin sensitivity than women with no diabetes family history, but increase insulin sensitivity to a greater extent with exercise training. This study aimed to determine whether differences in circulating concentrations of adiponectin and leptin, and adipose tissue expression of their genes and receptors played a role. Women offspring of patients with type 2 diabetes mellitus (n = 34; age, 35.6 ± 7.0 years; body mass index, 28.1 ± 5.1 kg/m2) and matched controls with no diabetes family history (n = 36; age, 33.6 ± 6.1 years; body mass index, 27.3 ± 4.7 kg/m2) participated. Blood and abdominal subcutaneous adipose tissue samples were obtained at baseline and after a controlled 7-week endurance-type exercise intervention (sessions were performed at 65%-80% of maximum heart rate). At baseline, no significant differences were observed between groups in circulating leptin or adiponectin concentrations, or expression of their genes or receptors. In response to exercise, plasma leptin decreased more in offspring than controls (−32.2% vs −7.3%, P = .005 for interaction); and the long isoform of the leptin receptor messenger RNA (mRNA) increased significantly only in the offspring (+39.4%, P = .026 vs +7.7%, P = .892). Leptin mRNA decreased similarly in both groups (−24.7% vs −25.0%, P < .05 for both). Furthermore, changes in plasma leptin (r = −0.432, P < .001) and leptin mRNA (r = −0.298, P = .019) correlated significantly with changes in insulin sensitivity. Plasma adiponectin decreased similarly in both groups (−12.1% vs −15.2%, P < .01 for both), but no significant changes were observed in adiponectin-related gene expression. This work shows that exercise training has differing effects on leptin-related variables between women with and without a diabetes family history and suggests that these molecular differences may contribute to the differential effects of exercise training on insulin sensitivity between these 2 groups.